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Can nicotine save your brain?

While the delivery system of smoking is unquestionably harmful, nicotine, the drug most associated with tobacco, may have medical applications. Becky McCall looks for answers.

Smoking may be a scourge on society but nicotine could be a blessing in disguise. – iStock

It's restless night number three in a row. Four hours of counting the cracks in the ceiling, then an hour’s sleep only to wake herself again with uncontrollable thrashing around. Most people’s muscles are paralysed during dreams, but Sarah, who suffers from Parkinson’s disease, physically acts hers out. During the day she’s exhausted and depressed about losing control of her muscles – and her life. But there is one consoling factor: if Sarah hadn’t smoked before her diagnosis, it’s likely her disease would be far worse by now.

A growing body of evidence suggests that smoking helps delay the progression of Parkinson’s disease, and potentially other cognitive diseases as well. These are statistics that rarely see the light of day; they are hidden from the public by layers of anti-smoking campaigns and health warnings.

More than half of Parkinson’s patients smoke, as do half of adolescents with severe Attention Deficit Hyperactivity Disorder (ADHD). The reasons why they smoke are uncertain, but research is finding some persuasive clues.

The proposed use of nicotine as therapy raises ethical issues, but the chemical’s effects depend on how it is delivered to the body.

Marcus Munafo is a researcher who specialises in nicotine addiction at the University of Bristol in the southwest of England. He points to reams of irrefutable evidence against smoking a deadly cocktail of toxins (see Nicotine: why it’s bad for you).

“Pure nicotine is a potentially lethal poison,” he says, “and as a constituent of tobacco smoke contributes to the increased risk of heart disease associated with smoking. In particular, it is known to raise blood pressure.”

But, he adds, it’s important to remember that risk is relative and nicotine per se is not as damaging as it is often perceived to be.

In fact, cigarettes contain almost 3,000 other chemicals that are considered more dangerous than nicotine. “People equate smoking with nicotine, saying all nicotine is bad for you. However, most of the harm from smoking comes from other chemicals.”

Munafo admits that the proposed use of nicotine as therapy raises ethical issues, but points out that the chemical’s effects depend on how it is delivered to the body.

“The addiction potential of pharmaceutical nicotine products such as patches and gum is quite low, certainly much lower than cigarettes,” he says. “With appropriate safeguards in place, there are no reasons to think that nicotine products could not be used safely for therapeutic purposes beyond their current approved use for smoking cessation.”

Studies of people with Alzheimer’s, Parkinson’s, schizophrenia and ADHD are raising concerns that by dismissing nicotine alongside smoking, we risk throwing out the baby with the bathwater.

Some scientists go so far as to say that for many patients suffering from cognitive diseases, it’s more important to avoid the severe consequences of advanced disease than to fear nicotine dependence.

Most findings have been sourced from studies that record disease outcomes in smokers and non-smokers, because this is the most prevalent use of nicotine in our society.

For example, a review of epidemiological studies led by researchers from the University of Washington, in Seattle, USA, and published in the journal Behavioural Brain Research in 2000, showed that non-smokers are twice as likely to develop Parkinson’s disease as smokers.

Another review of 44 previous studies, published in the U.S. journal Annals of Neurology in 2002, found that smokers have a 60 per cent lower risk of developing the disease.

Nicotine may help give dementia patients up to six extramonths of independent living.

At the 2008 Federation of European Neuroscience Societies conference in Geneva, Switzerland, behavioural pharmacologist Ian Stolerman of King’s College London reported that, in rats, nicotine improves concentration and quickens responses.

When allowed to concentrate fully, the animals managed to complete a task accurately 80 per cent of the time, but this figure dropped to 55 per cent when they were distracted by noise and flashing lights.

When nicotine was given to distracted rats, however, their accuracy rose to 85 per cent. Stolerman believes that – given time to translate these findings into a clinical therapy – nicotine may help give dementia patients up to six extra months of independent living.

Clinical findings relating to nicotine use and Alzheimer’s disease vary. But according to a review led by Marina Picciotto of Yale University in New Haven, Connecticut, and published in the U.S. journalFrontiers in Bioscience in 2008, the beneficial effects of nicotine seem to be outweighed by an increase in strokes linked to smoking.

However, abnormal proteins found at high levels between nerve cells in the brains of Alzheimer’s sufferers (known as amyloid-α and amyloid plaques) are reduced in both Alzheimer’s patients and in other elderly patients who smoke.

Taken together, these studies indicate that some component of cigarette smoke may protect against diseases involving nerve degeneration. In the absence of other effective therapies for these debilitating diseases, scientists are taking nicotine seriously.

Picciotto, a psychiatric scientist at Yale’s School of Medicine, has been investigating the role of nicotine in cognitive diseases at a biochemical and at a molecular level.

“In animal studies, if you get the dose and the regimen right, then nicotine can protect against nearly any cognitive disease model, whether stroke, Alzheimer’s or Parkinson’s,” she says. “Nicotine has also been shown to encourage dopamine release from neurones that would be lost in Parkinson’s disease.”

Nicotine could potentially slow progression of Parkinson’s

disease but is unlikely to reverse it.

Dopamine, a neurotransmitter or chemical messenger in the brain, is released after nicotine activates nicotinic receptors in the midbrain. These receptors in turn activate regions responsible for movement and motivation, as well as addiction behaviour.

“In patients with Parkinson’s disease, neurones are lost in these two regions. So stimulation of any remaining neurones with nicotine could help prevent further decline,” explains Picciotto.

If nicotine does preserve neurones, then diagnosing and treating patients before neurones are lost is vital; once gone, they cannot be replaced. Nicotine could potentially slow progression of Parkinson’s disease but is unlikely to reverse it.

Picciotto believes that a clinical study to establish the extent of nicotine’s protective effect in the early stages of the disease is essential.

At this stage, however, it’s almost impossible to predict who will develop Parkinson’s, and by the time it’s diagnosed, 60 to 70 per cent of neurones have already been lost and cannot be regained.

Should nicotine be sold in its current form, such as a patch,lozenge or spray, or as a specialised pharmaceutical product?

The power of nicotine in the human nervous system has been known since the early 20th century. Nicotine mimics a neurotransmitter called acetylcholine, and is a chemical signal sent between nerve cells.

The receptor in the nerve cell’s surface, called the nicotinic acetylcholine receptor, can be open, closed or insensitive. Both nicotine and acetylcholine affect the entire body, including the brain, heart and other muscles.

It’s the receptors in the brain attracting the attention of scientists. These receptors are involved in emotion, concentration and feelings of pleasure due to their high concentration in the limbic region of the brain, which is associated with emotion and reward.

But the crux of the matter is this: if nicotine is to be used therapeutically, then the properties that confer beneficial effects need to be separated from the addictive ones.

Indeed, all drugs approved for use in humans strive to maximise efficacy and minimise side effects. It’s just that in this case, the side effects are well known and clearly associated with death and disease.

The question then arises: should nicotine be sold in its current form, such as a patch, lozenge or spray, or as a specialised pharmaceutical product?

It’s likely that pharmaceutical products that work on the brain’s nicotinic receptors will be available via prescription in the next few years; a handful of companies already have products in clinical trials.

As drug targets, the nicotinic receptors are difficult, because of both their structure and function. There are an unknown number of receptor subtypes, but they are all composed of five subunits, called alpha (α) and beta (β) units.

Studies have shown that different subtypes have particular functions, and each are related to specific diseases.

Further research into the roles and sensitivities of the many different subtypes is central to teasing out those that exert a beneficial effect from those that induce dependence.

As Piciotto explains, “Overwhelming evidence suggests that addiction relies on activity at the highest affinity nicotinic receptors with subunits α4 and β2, so it’s preferable to avoid activating these receptors.”

Yet developing drugs that target only receptors with a beneficial effect is akin to trying to remove the ace of diamonds from a house of cards without causing it to fall.

Still, a number of companies are developing compounds that not only stimulate these receptors but also make them more likely to be activated by acetylcholine produced naturally in the body.

Even one of the world's largest cigarette manufacturers, R.J. Reynolds Tobacco, started a chemicals arm for developing therapeutics based on the activity of neuronal nicotinic receptors (NNR).

Targacept, now an independent company based in North Carolina, has shown that the nicotinic receptor subtype known as α7 is a key regulator of cognitive function. TC-5619, the lead product candidate in Targacept’s α7 NNR program, is currently in clinical trials.

William S. Caldwell, vice president of drug discovery and development for Targacept, explains that the company discovered and synthesised completely new compounds that target only those neuronal nicotinic receptors that regulate the beneficial effects.

“By normalising the activity of under-stimulated NNRs with these novel substances, therapeutic benefits have been demonstrated in a number of human clinical studies…[of] age associated memory impairment and mild cognitive impairment.”

He emphasises that the mode of administration is a very important factor in addiction.

“The abuse liability and dependence potential of nicotine replacement therapies like the patch or gum are very low when compared to that of cigarettes due to the slower absorption rate of nicotine from these products. Since the preferred route of administration for our selective NNR compounds is by mouth, resulting in slower absorption [than via inhalation], the abuse potential of our products is extremely low.”

And as Munafo of the University of Bristol points out, most of us regularly use potentially addictive drugs. “Is nicotine really so different?” he asks. “Many of us regularly use caffeine or alcohol and it doesn’t have much of an impact on our lives.”

Maybe he's right and it all boils down to public perception: a walk along any modern high street will tell you coffee is trendy, while shivering in the doorway of a smoke-free public space sucking on a cigarette is seen as anti-social, unhealthy and very passé.

But according to Amanda Sandford, research manager at British organisation Action on Smoking and Health, which aims to reduce smoking, there are compelling reasons for this perception.

“While using nicotine may have a protective effect for a very limited number of conditions, smoking is responsible for over 5.2 million deaths a year globally, so the emphasis on getting people to quit smoking and trying to dissuade children from ever taking it up must continue,” she says.

Yet it seems that – contrary to all common sense – patients with cognitive diseases who also smoke seem to fare better than their non-smoking counterparts.

Even more surprising is that an effective means of preventing or treating some of the world’s most challenging diseases could emerge from public health enemy number one.